JPH08505398A

JPH08505398A - Hexadentate ligands useful as radiographic imaging agents

Info

Publication number: JPH08505398A
Application number: JP6516246A
Authority: JP
Inventors: ニューマン、ウィリアム・エル; ラジャゴパラン、ラグハーヴァン
Original assignee: マリンクロット・メディカル・インコーポレイテッド
Priority date: 1993-01-06
Filing date: 1994-01-04
Publication date: 1996-06-11
Also published as: EP0690727A1; WO1994015647A1; AU6085294A; EP0690727A4

Abstract

(57)【要約】本発明は、特に、放射性核種との錯体形成に適し、かつ一般診断目的用イメージング剤として有用である、予め編成した新規六座配位子類に関する。 (57) [Summary] The present invention relates to novel pre-organized hexadentate ligands which are particularly suitable for complex formation with radionuclides and are useful as imaging agents for general diagnostic purposes.

Description

【発明の詳細な説明】放射線撮影イメージング剤に有用な六座配位子類この出願は、１９９０年１２月１４日に出願された米国特許出願第０７／６２７，１７６号の一部継続出願である。発明の背景本発明は、放射性核種錯体を形成するための新規配位子類、該配位子類を組み込んでいる新規錯体、該錯体の製法、該錯体が含まれているイメージング剤および該イメージング剤を用いるイメージング法に関する。骨格構造、器官または組織を可視化するための放射線撮影イメージング剤は、生物学および医学研究、および診断法の分野でよく知られている。このようなイメージング達成方法は、一般に、生物学的対象に投与したとき、研究しようとする特定の骨格構造、器官または組織内に局在化される放射性薬剤の調製を含んでいる。局在化された放射性薬剤は、次に、放射線検出器、例えば、トラバーシングスキャナまたはシンチレーションカメラにより追跡、プロットされ、またはシンチフォトグラフィーにかけられる。検出された放射活性薬剤の分布および相対強度は、薬剤が取り込まれた組織の位置を示すものであり、また異常の存在、病理学的状態なども示す。一般に、放射線撮影イメージング剤は、放射性核種標識された化合物、例えば、テクネチウム９９ｍ、レニウム１８６またはレニウム１８８、または他の適用出来る放射性核種等の錯体を、適切なキャリアーおよび補助剤、例えば、患者への注射または吸引に適した運搬媒体、生理的緩衝液および塩などと共に含んで成るものである。発明の詳細な説明本発明は、特に、放射性核種との錯体形成に適し、かつ一般診断目的用イメージング剤として有用である、予め編成した新規六座配位子類に関する。特に、本発明は、一般式式中、Ｒ₁、Ｒ₂およびＲ₃は、同じかまたは異なっており、水素、および、アルキル、アリール、ヒドロキシ、アルコキシ、モノ−またはポリ−ヒドロキシアルキル、モノ−またはポリ−アルコキシアルキル、アルコキシカルボニルおよびカルバモイルから成る群から選択される、２ないし１０の炭素原子を有する有機化合物から成る群から選択され；１およびｍは、同じかまたは異なっていても良く、１から６であり；ＱおよびＺは、同じかまたは異なっていても良く、Ｏ、ＮまたはＳ原子であり；ＸおよびＹは、同じかまたは異なっていても良く、式中、Ｒ₄、Ｒ₅およびＲ₆は、同じかまたは異なっていても良く、水素、および、アルキル、アリール、ヒドロキシ、アルコキシ、モノ−またはポリ−ヒドロキシアルキル、モノ−またはポリ−アルコキシアルキル、アルコキシカルボニル、アミノ、アルキルアミノ、アミノアルキル、およびカルバモイルから成る群から選択される、２ないし１０の炭素原子を有する有機化合物類から成る群から選択される、を有する、新規配位子類に関する。好ましい実施態様において、本発明の配位子類は、上記一般式Ｉで、式中Ｒ₁ が水素であり；Ｒ₂およびＲ₃がメチル基であり；１およびｍが３であり；ＱおよびＺが酸素原子であり；ＸおよびＹが同じで上記定義したとおりのものを有する。更に好ましい実施態様では、ＸおよびＹが同じであって、式中、Ｒ₄およびＲ₅がフェニル基である。上記の新規配位子類は、放射線撮影イメージング剤として使用される放射性核種内に取り込まれ得る。本発明の錯体類は、前記配位子類の１つを、放射性核種含有溶液と、放射性核種錯体形成反応条件下で反応させることにより、製造する。特に、テクネチウム剤が望まれる場合、反応を、テクネチウム９９ｍ錯体形成反応条件下、過テクネテート溶液で行う。次いで、溶媒を適切な方法、例えばエバポレーションにより除去する。その後、錯体類を医薬的に許容され得る媒体中に溶解または懸濁して、患者への投与用に調製する。本発明の配位子類は、商業的に入手出来る出発物質、例えば２−ニトロベンジルブロミド、ヒドロキシエチルエチレンジアミン等から、下記実施例に記載した標準的合成法により製造出来る。本発明の放射性核種錯体は、一般式式中、Ｍは、適切な放射性核種、例えば、テクネチウムまたはレニウムであり、Ｒ₁、Ｒ₂、Ｒ₃、ｌ、ｍ、Ｘ、Ｙ、ＱおよびＺは、上記式Ｉで定義したものと同じである、を持ち得る。好ましい実施態様において、一般式IIを有するテクネチウム放射性核種錯体は、過テクネテート溶液および、上記一般式Ｉで示される配位子、但し、式中Ｒ₁はメチル基であり、Ｒ₂は水素であり、Ｒ₃はメチル基であり、ｌ＝３、ｍ＝３、Ｑ＝Ｏ、Ｚ＝Ｏ、ＸおよびＹは同じであって上記定義したとおりである、とから形成され得る。放射性核種を含有する溶液は、知られている手法で放射性核種生成源から得ることが出来る。例えば、テクネチウム錯体を形成させる場合、過テクネテート溶液は知られている手法でテクネチウム生成源から得ることが出来る。次いで、放射性核種錯体形成反応を適切な反応条件下で行う。例えば、テクネチウム９９ｍ錯体形成反応は、テクネチウム錯体形成温度下、例えば、２０℃ないし１００℃ で１０分ないし数時間かけて行う。適切な配位子類を、放射性核種錯体形成量よりも大過剰量で使用するのが好ましい。例えば、テクネチウム錯体を形成させる場合、少なくとも過テクネテート溶液よりも１０倍過剰量の配位子類を使用する。過テクネテートは、テクネテート錯体形成量、例えば、約１０⁶ないし１０¹² モル量で使用する。本発明は、また医薬的に許容され得る放射能学的媒体と共に、上記放射性核種錯体をイメージングに十分な量含有するイメージング剤にも関する。放射能学的媒体は、注射または吸引に適するべきであり、例えば、ヒト血清アルブミン；水性緩衝溶液、例えば、トリス（ヒドロメチル）アミノメタン（およびその塩）、リン酸塩、クエン酸塩、重炭酸塩等；滅菌水；生理食塩水；および塩化物およびまたはジカーボネート塩、または正常血漿カチオン、例えば、Ｃa²⁺、Ｎa⁺、Ｋ⁺ 、Ｍg²⁺を含有する平衡化イオン溶液である。本発明のイメージング剤の放射能学的媒体中の濃度は、満足のいくイメージングを提供するに十分であるべきであり、例えば、水性溶液を使用する場合、その用量は、約１.０ないし５０ミリキュリーである。イメージング剤は、患者の体内で約１ないし３時間留まるように投与すべきであるが、それより長短両方の期間が許容出来る。それ故に、水性溶液１ないし１０mlを含有する便利なアンプルを用意出来る。イメージングは、通常の方法で行うことが出来、例えば、適切なイメージングを提供するに十分量の組成物を注射し、次いで、適切な機器、例えばガンマカメラでスキャンニングする。本発明の錯体類は、下記実施例に従い製造出来る。実施例１の製造アセチルアセトン（１.５１g、１５.１ミリモル）をメタノール（２０ml）中４,５−ジアミノ−１,８−ビス（デフェニルホスホロ）−オクタン（３.４０g、７.５０ミリモル）の溶液に加え、混合物を５分間加熱して還流させ、冷まして周辺温度で１時間攪拌した。溶媒を減圧下で除去し、残渣をヘキサン（５×５０ ml）で摩砕した。集め合わせたヘキサン抽出物を蒸発濃縮して、粘性油状物を得た。この粗製物を放射状クロマトグラフィー（ＳiＯ₂、３：１ヘキサン−酢酸エチル）により精製して、所望の配位子を黄色粘性油状物として得た。Ｈ−ＮＭＲ（トルエン−ｄ₈）；δ１１.２２（ｄ，２Ｈ），６.９５−７.５５（ｍ，２０Ｈ），４.４０（ｓ，２Ｈ），２.１０（ｍ，２Ｈ），１.９５−２.０５（多数のシングレット，１２Ｈ），.９５−２.０５（ｍ，１２Ｈ） ¹³Ｃ−ＮＭＲ（トルエン−ｄ₈）；δ１９５.５（ｓ），１６２.４（ｓ），１４０.５（ｓ），１４０.３（ｓ），１４０.２（ｓ），１３４.０（ｄ），１３３ .８（ｄ），１３３.７（ｄ），１３３.６（ｄ），１３３.４（ｄ），１３２.５（ｄ），１３２.４（ｄ），１３１.４（ｄ），１３１.３（ｄ），９５.９（ｄ），５８.５（ｄ），５４.８（ｄ），３８.３（−ＣＨ₂−，Ｊ_pccc＝１２.３Ｈz），３５.０（−ＣＨ₂−，Ｊ_pccc＝１２.３Ｈz），２９.０（ｑ），２８.６（−ＣＨ₂ −，Ｊ_pcc＝１２.６Ｈz），２８.５（−ＣＨ₂−，Ｊ_pcc＝７.５Ｈz），２３.０（−ＣＨ₂−Ｐ−，Ｊ_pc＝１６.９Ｈz），１９.２（ｑ） ³¹Ｐ−ＮＭＲ（トルエン−ｄ₈）；δ−１８.０実施例２の製造４−メトキシサリチルアルデヒド（２.４３ｇ、１６.０ミリモル）をメタノール（２５ml）中４,５−ジアミノ−１,８−ビス（ジフェニルホスフィン）オクタン（３.６０ｇ、７.９９ミリモル）の溶液に加え、得られた黄色混合物を５分間加熱して潅流させ、冷まして周辺温度で１時間攪拌した。溶媒を減圧下で除去し、黄色残渣をヘキサン（３×５０ml）で摩砕して、配位子５.７７ｇ（９３％）を黄色無定形固体として得た。 ¹³Ｃ−ＮＭＲ（ベンゼン−ｄ₆）；δ１６５.６（ｄ），１６５.５（ｓ），１６４.６（ｓ），１４０.３（ｓ），１４０.２（ｓ），１４０.０（ｓ），１３５ .７（ｓ），１３５.０（ｄ），１３４.８（ｄ），１３４.０（ｄ），１３３.９（ｄ），１３３.８（ｄ），１３３.７（ｄ），１３３.６（ｄ），１３３.４（ｄ），１３１.６（ｄ），１３１.５（ｄ），１１３.２（ｄ），１０７.４（ｄ），１０１.８（ｄ），７３.３（ｄ），５５.１（ｑ），３４.３（−ＣＨ₂−，Ｊ_pcc _c ＝１２.２Ｈz），２８.４（−ＣＨ₂−，Ｊ_pcc＝１２.７Ｈz），２３.１（−ＣＨ₂−Ｐ−，Ｊ_pc＝１７.０Ｈz） ³¹Ｐ−ＮＭＲ（ベンゼン−ｄ₆）：δ−１７.８上記は、本発明の好ましい実施態様の説明であるが、本発明を何等限定するすることを意図するものではない。むしろ、細部にわたる多くの修飾、変形および変化は、本発明の範囲内で為される得るものである。DETAILED DESCRIPTION OF THE INVENTION Hexadentate Ligands Useful for Radiographic Imaging Agents This application is a continuation-in-part of US patent application Ser. No. 07 / 627,176, filed December 14, 1990. Is. BACKGROUND OF THE INVENTION The present invention is directed to novel ligands for forming radionuclide complexes, novel complexes incorporating the ligands, methods of making the complexes, imaging agents containing the complexes and the imaging. The present invention relates to an imaging method using an agent. Radiographic imaging agents for visualizing skeletal structures, organs or tissues are well known in the fields of biological and medical research, and diagnostics. Such methods of achieving imaging generally involve the preparation of radiopharmaceuticals which, when administered to a biological subject, are localized within the particular skeletal structure, organ or tissue under study. The localized radiopharmaceutical is then tracked, plotted, or subjected to scintigraphy with a radiation detector, such as a traversing scanner or scintillation camera. The detected distribution and relative intensities of the radioactive drug indicate the location of the tissue in which the drug is taken up, and also indicate the presence of abnormalities, pathological conditions, etc. In general, radiographic imaging agents are prepared by incorporating radionuclide-labeled compounds such as technetium 99m, rhenium 186 or rhenium 188, or other applicable complexes of radionuclides into suitable carriers and adjuvants, eg, to patients. It comprises a carrier medium suitable for injection or inhalation, physiological buffer and salts. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pre-organized hexadentate ligands that are particularly suitable for complexing with radionuclides and are useful as imaging agents for general diagnostic purposes. In particular, the invention has the general formula Wherein R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, alkoxycarbonyl. And carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms; 1 and m may be the same or different and are 1 to 6; Q and Z Are the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, New ligands having alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl selected from the group consisting of organic compounds having 2 to 10 carbon atoms. In a preferred embodiment, the ligands of the invention are of general formula I above, wherein R ₁ is hydrogen; R ₂ and R ₃ are methyl groups; 1 and m are 3; Z is an oxygen atom; X and Y are the same and have the same meaning as defined above. In a further preferred embodiment, X and Y are the same and In the formula, R ₄ and R ₅ are phenyl groups. The novel ligands described above can be incorporated into radionuclides used as radiographic imaging agents. The complexes of the present invention are prepared by reacting one of the above ligands with a radionuclide-containing solution under radionuclide complex forming reaction conditions. In particular, if a technetium agent is desired, the reaction is carried out in a pertechnetate solution under technetium 99m complex formation reaction conditions. The solvent is then removed by a suitable method, such as evaporation. The complexes are then dissolved or suspended in a pharmaceutically acceptable vehicle and prepared for administration to a patient. The ligands of the present invention can be prepared from commercially available starting materials such as 2-nitrobenzyl bromide, hydroxyethylethylenediamine, etc. by standard synthetic methods described in the Examples below. The radionuclide complex of the present invention has the general formula Wherein M is a suitable radionuclide, such as technetium or rhenium, R ₁ , R ₂ , R ₃ , l, m, X, Y, Q and Z are the same as defined in formula I above. Can have. In a preferred embodiment, the technetium radionuclide complex having general formula II comprises a pertechnetate solution and a ligand of general formula I above, wherein R ₁ is a methyl group and R ₂ is hydrogen. , R ₃ is a methyl group and l = 3, m = 3, Q = O, Z = O, X and Y are the same and are as defined above. The solution containing the radionuclide can be obtained from the radionuclide generating source by a known method. For example, in the case of forming a technetium complex, a pertechnetate solution can be obtained from a technetium producing source by a known method. The radionuclide complex formation reaction is then carried out under suitable reaction conditions. For example, the technetium 99m complex formation reaction is carried out at a technetium complex formation temperature, for example, at 20 ° C. to 100 ° C. for 10 minutes to several hours. It is preferred to use the appropriate ligands in large excess over the radionuclide complex-forming amount. For example, when forming a technetium complex, at least a 10-fold excess of ligands over the pertechnetate solution is used. The pertechnetate is used in a technetate complex-forming amount, for example about 10 ⁶ to 10 ¹² molar. The present invention also relates to an imaging agent containing the above radionuclide complex in an amount sufficient for imaging together with a pharmaceutically acceptable radiological medium. The radiological medium should be suitable for injection or inhalation, eg human serum albumin; aqueous buffer solutions, eg tris (hydromethyl) aminomethane (and its salts), phosphates, citrates, bicarbonates. Salts and the like; sterile water; saline; and chloride and / or dicarbonate salts, or equilibrated ionic solutions containing normal plasma cations such as Ca ²⁺ , Na ⁺ , K ⁺ , Mg ²⁺ . The concentration of the imaging agent of the present invention in the radiological medium should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dose is about 1.0 to 50. It's Millicury. The imaging agent should be administered so that it remains in the patient's body for about 1 to 3 hours, but both longer and shorter periods are acceptable. Therefore, a convenient ampoule containing 1 to 10 ml of an aqueous solution can be prepared. Imaging can be carried out in the usual way, eg by injecting a sufficient amount of the composition to provide suitable imaging and then scanning with a suitable instrument, eg a gamma camera. The complexes of the present invention can be manufactured according to the following examples. Example 1 Preparation of acetylacetone (1.51 g, 15.1 mmol) in methanol (20 ml) solution of 4,5-diamino-1,8-bis (dephenylphosphoro) -octane (3.40 g, 7.50 mmol). In addition, the mixture was heated at reflux for 5 minutes, cooled and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with hexane (5 x 50 ml). The combined hexane extracts were concentrated by evaporation to give a viscous oil. The crude was purified by radial chromatography (SiO ₂ , 3: 1 hexane-ethyl acetate) to give the desired ligand as a yellow viscous oil. H-NMR (toluene-d ₈ ); δ 11.22 (d, 2H), 6.95-7.55 (m, 20H), 4.40 (s, 2H), 2.10 (m, 2H), 1.95-2.05 (many singlets, 12H), .95-2.05 (m, 12H) ¹³ C-NMR (toluene-d ₈ ); δ 195.5 (s), 162.4 (s). ), 140.5 (s), 140.3 (s), 140.2 (s), 134.0 (d), 133.8 (d), 133.7 (d), 133.6 (d). ), 133.4 (d), 132.5 (d), 132.4 (d), 131.4 (d), 131.3 (d), 95.9 (d), 58.5 (d). , 54.8 (d), 38.3 ( -CH 2 -, J pccc = 12.3Hz), 3 5.0 (-CH 2 -, J pccc = 12.3Hz), 29.0 (q), _{_{28.6 (-CH 2 -, J pcc}} = 12.6Hz), 28.5 ( _{_{-CH 2 -, J pcc = 7.5Hz}} ), 23.0 (-CH 2 -P-, J pc = 16.9Hz), 19.2 (q) 31 P-NMR ( toluene -d _8); δ -18.0 Example 2 Preparation of 4-methoxysalicylaldehyde (2.43 g, 16.0 mmol) in methanol (25 ml) of 4,5-diamino-1,8-bis (diphenylphosphine) octane (3.60 g, 7.99 mmol). Upon addition to the solution, the resulting yellow mixture was heated to perfusion for 5 minutes, cooled and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and the yellow residue was triturated with hexane (3 x 50 ml) to give 5.77 g (93%) of the ligand as a yellow amorphous solid. ¹³ C-NMR (benzene-d ₆ ); δ 165.6 (d), 165.5 (s), 164.6 (s), 140.3 (s), 140.2 (s), 140.0. (S), 135.7 (s), 135.0 (d), 134.8 (d), 134.0 (d), 133.9 (d), 133.8 (d), 133.7 ( d), 133.6 (d), 133.4 (d), 131.6 (d), 131.5 (d), 113.2 (d), 107.4 (d), 101.8 (d). ), 73.3 (d), 55.1 (q), 34.3 (-CH 2 -, J pcc c = 12.2Hz), 28.4 (-CH 2 -, J pcc = 12.7Hz) , 23.1 (-C H ₂ -P-, J _pc = 17.0 Hz) ³¹ P-NMR (benzene-d ₆ ): δ-17.8 The above is a description of preferred embodiments of the present invention. It is not intended to limit the present invention in any way. . Rather, many modifications, variations and changes in detail can be made within the scope of the invention.

Claims

[Claims] 1. The ligand has the general formula: Wherein R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, alkoxycarbonyl. And carbamoyl selected from the group consisting of organic compounds having 2 to 10 carbon atoms; 1 and m may be the same or different and are 2 to 5; Q and Z Are the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, Selected from the group consisting of alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms, A ligand useful in the formation of radionuclide complexes. 2. A ligand according to claim 1 wherein either R ₁ and R ₂ or R ₂ and R ₃ can together form a 5 to 7 membered carbocycle or heterocycle. 3. The ligand according to claim 1, wherein R ₁ and R ₃ are methyl groups; R ₂ is hydrogen; 1 and m are 3; and Q and Z are oxygen atoms. 4. R ₁ and R ₃ are methyl groups; R ₂ is hydrogen; 1 and m are 3; Q and Z are oxygen atoms; X and Y are However, the ligand according to claim 1, wherein R ₄ and R ₅ are phenyl groups. 5. R ₁ is hydrogen; R ₂ and R ₃ together form one carbocycle; 1 and m are 3; Q and Z are oxygen atoms; X and Y are However, the ligand according to claim 1, wherein R ₄ and R ₅ are phenyl groups. 6. The ligand according to claim 5, wherein the carbocycle is methoxybenzene. 7. General formula: Wherein M is a radionuclide; R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or Selected from the group consisting of organic compounds having 2 to 10 carbon atoms selected from the group consisting of poly-alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and from 2 5; Q and Z may be the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, Selected from the group consisting of alkoxycarbonyl, amino, alkylamino, aminoalkyl, or carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms, A radionuclide complex having: 8. One of R ₁ and R ₂ or R ₂ and R _3, taken together, to one 5 can form a carbocyclic or heterocyclic ring 7 membered, complex according Claim 7. 9. 8. The complex according to claim 7, wherein M is technetium or rhenium. Ten. R ₁ is a methyl group; R ₂ is hydrogen; R ₃ is a methyl group; 1 = 3, m = 3, Q = O, Z = O, and X and Y are the same. The complex according to claim 7. 11. R ₁ and R ₃ are methyl groups; R ₂ is hydrogen; 1 and m are 3; Q and Z are oxygen atoms; X and Y are However, R ₄ and R ₅ are phenyl groups, The complex according to claim 7. 12. R ₁ is hydrogen; R ₂ and R ₃ together form a carbocycle; 1 and m are 3; Q and Z are oxygen atoms; X and Y are However, R ₄ and R ₅ are phenyl groups, The complex according to claim 7. 13. The complex according to claim 12, wherein the carbocycle is methoxybenzene. 14. General formula: Wherein M is a radionuclide; R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or Selected from the group consisting of organic compounds having 2 to 10 carbon atoms selected from the group consisting of poly-alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and from 2 5; Q and Z may be the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, Selected from the group consisting of alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms, A method for producing a radionuclide complex having: a solution containing a radionuclide, and a general formula: Wherein _{_{_{R 1, R 2, R 3}}} , l, m, X, Y, Q and Z comprises reacting a ligand having the same as those defined above, process. 15. 15. The process according to claim 14, wherein either R ₁ and R ₂ or R ₂ and R ₃ can together form a 5 to 7 membered carbocycle or heterocycle. 16. The method according to claim 14, wherein M is technetium or rhenium, and the radionuclide containing the solution is a pertechnetate or perrenate solution, respectively. 17. General formula: Wherein M is a radionuclide; R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or Selected from the group consisting of organic compounds having 2 to 10 carbon atoms selected from the group consisting of poly-alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and from 2 5; Q and Z may be the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, Selected from the group consisting of alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms, And a pharmaceutically acceptable radiological medium. 18. 18. The imaging agent according to claim 17, wherein either R ₁ and R ₂ , or R ₂ and R ₃ can be combined to form one 5- to 7-membered carbocyclic or heterocyclic ring. 19. The imaging agent according to claim 17, wherein M is technetium or rhenium. 20. The vehicle is suitable for injection or inhalation and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, saline and equilibrated ionic solutions containing chloride salts, bicarbonates or plasma cations. The imaging agent according to claim 17, which is one. twenty one. 18. The imaging agent according to claim 17, wherein the concentration of the complex in the medium is about 1.0 to 50 millicuries. twenty two. General formula: Wherein M is a radionuclide; R ₁ , R ₂ and R ₃ are the same or different and are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or Selected from the group consisting of organic compounds having 2 to 10 carbon atoms selected from the group consisting of poly-alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and from 2 5; Q and Z may be the same or different and are O, N or S atoms; X and Y may be the same or different, Wherein R ₄ , R ₅ and R _{6, which} may be the same or different, are hydrogen and alkyl, aryl, hydroxy, alkoxy, mono- or poly-hydroxyalkyl, mono- or poly-alkoxyalkyl, Selected from the group consisting of alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl, selected from the group consisting of organic compounds having 2 to 10 carbon atoms, And a pharmaceutically acceptable radiological medium, injecting an imaging agent in an amount sufficient to provide suitable imaging, and then by a suitable scanning device. A radiographic imaging method comprising scanning. twenty three. R ₁ and R _2, or any of R ₂ and R ₃ together, to one 5 can form a carbocyclic or heterocyclic ring 7 membered, imaging method in the range 22 claim of claim. twenty four. The imaging method according to claim 22, wherein M is technetium or rhenium. twenty five. The vehicle is suitable for injection or inhalation and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, saline and equilibrated ionic solutions containing chloride salts, bicarbonates or plasma cations. The imaging method according to claim 22, wherein the imaging method is used. 26. 23. The imaging method according to claim 22, wherein the concentration of the complex in the medium is about 1.0 to 50 millicuries.